Sex-specific resilience of neocortex to food restriction.

Mammals have evolved sex-specific adaptations to reduce energy usage in times of food scarcity. These adaptations are well described for peripheral tissue, though much less is known about how the energy-expensive brain adapts to food restriction, and how such adaptations differ across the sexes. Here, we examined how food restriction impacts energy usage and function in the primary visual cortex (V1) of adult male and female mice. Molecular analysis and RNA sequencing in V1 revealed that in males, but not in females, food restriction significantly modulated canonical, energy-regulating pathways, including pathways associated waith AMP-activated protein kinase, peroxisome proliferator-activated receptor alpha, mammalian target of rapamycin, and oxidative phosphorylation. Moreover, we found that in contrast to males, food restriction in females did not significantly affect V1 ATP usage or visual coding precision (assessed by orientation selectivity). Decreased serum leptin is known to be necessary for triggering energy-saving changes in V1 during food restriction. Consistent with this, we found significantly decreased serum leptin in food-restricted males but no significant change in food-restricted females. Collectively, our findings demonstrate that cortical function and energy usage in female mice are more resilient to food restriction than in males. The neocortex, therefore, contributes to sex-specific, energy-saving adaptations in response to food restriction.

Cortical wiring by synapse type-specific control of local protein synthesis.

Neurons use local protein synthesis to support their morphological complexity, which requires independent control across multiple subcellular compartments up to the level of individual synapses. We identify a signaling pathway that regulates the local synthesis of proteins required to form excitatory synapses on parvalbumin-expressing (PV+) interneurons in the mouse cerebral cortex. This process involves regulation of the TSC subunit 2 (Tsc2) by the Erb-B2 receptor tyrosine kinase 4 (ErbB4), which enables local control of messenger RNA {mRNA} translation in a cell type-specific and synapse type-specific manner. Ribosome-associated mRNA profiling reveals a molecular program of synaptic proteins downstream of ErbB4 signaling required to form excitatory inputs on PV+ interneurons. Thus, specific connections use local protein synthesis to control synapse formation in the nervous system.

Distinct molecular programs regulate synapse specificity in cortical inhibitory circuits.

How neuronal connections are established and organized into functional networks determines brain function. In the mammalian cerebral cortex, different classes of GABAergic interneurons exhibit specific connectivity patterns that underlie their ability to shape temporal dynamics and information processing. Much progress has been made toward parsing interneuron diversity, yet the molecular mechanisms by which interneuron-specific connectivity motifs emerge remain unclear. In this study, we investigated transcriptional dynamics in different classes of interneurons during the formation of cortical inhibitory circuits in mouse. We found that whether interneurons form synapses on the dendrites, soma, or axon initial segment of pyramidal cells is determined by synaptic molecules that are expressed in a subtype-specific manner. Thus, cell-specific molecular programs that unfold during early postnatal development underlie the connectivity patterns of cortical interneurons.

Activity-Dependent Gating of Parvalbumin Interneuron Function by the Perineuronal Net Protein Brevican.

Activity-dependent neuronal plasticity is a fundamental mechanism through which the nervous system adapts to sensory experience. Several lines of evidence suggest that parvalbumin (PV+) interneurons are essential in this process, but the molecular mechanisms underlying the influence of experience on interneuron plasticity remain poorly understood. Perineuronal nets (PNNs) enwrapping PV+ cells are long-standing candidates for playing such a role, yet their precise contribution has remained elusive. We show that the PNN protein Brevican is a critical regulator of interneuron plasticity. We find that Brevican simultaneously controls cellular and synaptic forms of plasticity in PV+ cells by regulating the localization of potassium channels and AMPA receptors, respectively. By modulating Brevican levels, experience introduces precise molecular and cellular modifications in PV+ cells that are required for learning and memory. These findings uncover a molecular program through which a PNN protein facilitates appropriate behavioral responses to experience by dynamically gating PV+ interneuron function.

Synergy between sphingosine 1-phosphate and lipopolysaccharide signaling promotes an inflammatory, angiogenic and osteogenic response in human aortic valve interstitial cells.

Given that the bioactive lipid sphingosine 1-phosphate is involved in cardiovascular pathophysiology, and since lipid accumulation and inflammation are hallmarks of calcific aortic stenosis, the role of sphingosine 1-phosphate on the pro-inflammatory/pro-osteogenic pathways in human interstitial cells from aortic and pulmonary valves was investigated. Real-time PCR showed sphingosine 1-phosphate receptor expression in aortic valve interstitial cells. Exposure of cells to sphingosine 1-phosphate induced pro-inflammatory responses characterized by interleukin-6, interleukin-8, and cyclooxygenase-2 up-regulations, as observed by ELISA and Western blot. Strikingly, cell treatment with sphingosine 1-phosphate plus lipopolysaccharide resulted in the synergistic induction of cyclooxygenase-2, and intercellular adhesion molecule 1, as well as the secretion of prostaglandin E2, the soluble form of the intercellular adhesion molecule 1, and the pro-angiogenic factor vascular endothelial growth factor-A. Remarkably, the synergistic effect was significantly higher in aortic valve interstitial cells from stenotic than control valves, and was drastically lower in cells from pulmonary valves, which rarely undergo stenosis. siRNA and pharmacological analysis revealed the involvement of sphingosine 1-phosphate receptors 1/3 and Toll-like receptor-4, and downstream signaling through p38/MAPK, protein kinase C, and NF-κB. As regards pro-osteogenic pathways, sphingosine 1-phosphate induced calcium deposition and the expression of the calcification markers bone morphogenetic protein-2 and alkaline phosphatase, and enhanced the effect of lipopolysaccharide, an effect that was partially blocked by inhibition of sphingosine 1-phosphate receptors 3/2 signaling. In conclusion, the interplay between sphingosine 1-phosphate receptors and Toll-like receptor 4 signaling leads to a cooperative up-regulation of inflammatory, angiogenic, and osteogenic pathways in aortic valve interstitial cells that seems relevant to the pathogenesis of aortic stenosis and may allow the inception of new therapeutic approaches.

Meta-analysis and literature review of techniques to achieve hemostasis in endoscopic sinus surgery.

BACKGROUND: Functional endoscopic sinus surgery (FESS) has been used as the standard of treatment for sinonasal disease in which medical therapy fails to ameliorate the disease. Intraoperative hemostasis is a crucial factor in FESS. Currently, ideal techniques for creating intraoperative hemostasis have yet to be clarified and standardized. We sought to better understand what variables can affect intraoperative blood loss and therefore improve surgical field outcomes. METHODS: A literature search was conducted using PubMed, OVID, MD Consult, and Micromedex with keywords including: FESS, intraoperative blood loss, hemorrhage, and vasoconstriction. The articles were then evaluated with regard to blood loss, surgical grade, and operative time. Eleven articles were cross-referenced to determine the most statistically significant techniques in 3 main categories: general anesthetics, preoperative steroids, and use of epinephrine. RESULTS: Analysis of the articles indicate that total intravenous anesthesia (TIVA) is statistically more beneficial than balanced anesthesia (BA), providing an average difference in blood loss of 75.3057 mL; the use of preoperative steroids is statistically more beneficial than placebo, with an improved difference in blood loss of 28 mL; and a trend toward hemostasis with the use of local anesthetics at a concentration of 1:200,000. CONCLUSION: Meta-analysis of 1148 patients concludes that hemostasis during FESS is best conducted using TIVA, preoperative steroids, and topical local anesthetic at a 1:200,000 concentration.

Viral and bacterial patterns induce TLR-mediated sustained inflammation and calcification in aortic valve interstitial cells.

BACKGROUND: Aortic stenosis shares some ethiopathological features with atherosclerosis and increasing evidence links Toll-like receptors (TLRs) to atherogenesis. METHODS: TLR-mediated inflammation and osteogenesis were investigated in human interstitial cells isolated from stenotic and non-stenotic aortic valves. TLR expression and signalling were evaluated by quantitative RT-PCR, flow cytometry, Western blot analysis, ELISA, and cytokine arrays. Osteogenesis was evaluated by measuring alkaline phosphatase activity. RESULTS: Interstitial cells from control valves express most TLRs, being TLR4 the most abundant, whereas cells from stenotic valves express higher TLR4 and TLR2 and lower TLR5 and TLR9 transcript levels. When pro-inflammatory pathways were analyzed, we observed that TLR4, TLR2 and TLR3 ligands induced an early activation of NF-κB and p38 MAPK activation in cells from control and stenotic valves. Strikingly, when TLRs sensing viral patterns were studied, a sustained TLR3-mediated activation of NF-κB, a κB-independent induction of catalytically active cyclooxigenase (COX)-2 and ICAM-1 expression, and induction of expression of several chemokines were observed. TLR4, but not TLR2, engagement produced a similar but NF-κB-dependent effect. Moreover, TLR3 and TLR4 agonists induced alkaline phosphatase expression and activity. CONCLUSIONS: Exposure of aortic valve interstitial cells to viral and Gram-negative bacteria molecular patterns induces distinct and long-term TLR-mediated pro-inflammatory and pro-osteogenic responses that might be relevant to the pathogenesis of degenerative aortic stenosis.

A novel use of a landmark to avoid injury of the anterior ethmoidal artery during endoscopic sinus surgery.

BACKGROUND: The aim of this study was to describe and correlate radiographically the anterior ethmoidal artery (AEA) to useful endoscopic surgical landmarks, such as the nasal beak (NB), nasal crest (NC), and axilla of the middle turbinate, because these are commonly encountered during endoscopic sinus surgery and skull base surgery. METHODS: A retrospective review and software analysis was performed by three independent observers. Measurements of distance and angulation from the AEA to the NC, NB, and axilla of the middle turbinate were performed. A total of 138 unique computed tomography (CT) scans performed at a university tertiary care center were evaluated. RESULTS: The average age of the patients whose scans were analyzed was 50.5 (range, 17-90 years) years of age. The gender distribution was 61 male and 89 female patients. After comparing the measurements to the three landmarks noted, it was determined that the NB had the most interpatient concordance and the least interobserver variability. The average distance between the NB and the AEA as it penetrates the lamina papyracea is 2.34 cm (variance, 0.07) at an angle of 45.21° from the Frankfurt horizontal line. CONCLUSION: The real advantage of this novel use of the NB as a landmark to identify the AEA is that it is easy to use, unobtrusive, and is not time-consuming. This relationship between the NB and the AEA is consistent across genders and ethnicities and is more valuable than others presented previously, which may be more variable.

Combined endoscopic and minitrephination techniques in the surgical management of frontal sinus type IV cell disease.

OBJECTIVE: The aim of the study was to present minimally invasive combined endoscopic and minitrephination techniques in the surgical management of frontal sinus type IV cell disease. METHODS: Case report of a 44-year-old man with localized pain in the right forehead. Computed tomography of the sinus revealed an opacified expanding type IV cell within the right frontal sinus, draining into the frontal sinus itself. An endoscopic approach through the frontal recess was not successful in reaching this cell. A minitrephination approach was then used and an endoscope was inserted through the trephination hole. Instruments were inserted endoscopically into the right frontal sinus through the frontal recess and then using direct endoscopic visualization through the minitrephination access, the frontal cell was opened and marsupialized. RESULTS: The patient recovered uneventfully with his localized frontal pain completely resolved 3 years after surgery. CONCLUSION: The minitrephination approach can be used to introduce an endoscope into the frontal sinus to assist in the surgical management of remote cephalad and lateral lesions within the sinus that are otherwise difficult to reach using endoscopic techniques alone.

Proteomics blood testing to distinguish chronic rhinosinusitis subtypes.

OBJECTIVES: To evaluate the potential of surface enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF-MS) proteomic profiling of serum samples to distinguish chronic rhinosinusitis subtypes. STUDY DESIGN: Translational study of serum samples from prospectively enrolled patients undergoing sinus surgery. METHODS: Patients undergoing endoscopic sinus surgery for chronic rhinosinusitis with nasal polyposis were prospectively enrolled in an ongoing, institutional review board approved proteomics study. SELDI-TOF-MS was performed on 42 serum samples in patients with chronic rhinosinusitis with nasal polyposis (15 patients diagnosed with allergic fungal rhinosinusitis, 10 patients with Samter's triad, and 17 with chronic rhinosinusitis with nasal polyposis). Classification tree analysis on protein spectra developed from peaks detected in the 0 to 100 kD range was performed to identify disease subtypes. RESULTS: SELDI-TOF-MS correctly identified patients with allergic fungal rhinosinusitis from serum samples with 84% sensitivity and 90% specificity, and correctly identified patients with Samter's triad with 88% sensitivity and 88% specificity in two subtype comparison groups. SELDI-TOF-MS correctly identified patients with allergic fungal rhinosinusitis with 76% sensitivity and 82% specificity, and correctly identified patients with Samter's triad with 80% sensitivity and 90% specificity in three subtype comparison groups. CONCLUSION: The study provides molecular evidence that allergic fungal rhinosinusitis is a discrete subtype of chronic rhinosinusitis. SELDI-TOF-MS is a promising technology that could lead to the development of a rapid blood test, to identify severe chronic rhinosinusitis subtypes. Further investigation into the utility of this technology is warranted.

The use of portable intraoperative computed tomography scanning for real-time image guidance: a pilot cadaver study.

BACKGROUND: This study was performed to assess the feasibility of using intraoperative computed tomography (CT) to provide real-time updates to image guidance systems (IGSs) during surgery. METHODS: The xCAT ENT portable intraoperative CT scanner (Xoran Technologies, Ann Arbor, MI) was used to acquire scans before, midway, and at the end of six cadaver dissections during the Southern States Rhinology Course, Augusta, GA, in October 2006. These scans were used to recalibrate three different IGSs used during the dissection. Time measurements were recorded and dosimetry was obtained from the cornea, sphenoid sinus (near the optic chiasm), and from the operative field during acquisition of the images. IGS accuracy was determined at the skull base and lamina papyracea. Surgeons were interviewed on benefits of real-time updates to the IGS after completion of dissections. RESULTS: The xCAT ENT scanner was compatible with all three IGS platforms. The average time to update the IGS was 13 minutes. Radiation doses to the cornea were 620 mrad per scan, and optic chiasm was 800 mrad/scan. The accuracy at the anterior skull base improved from 1.58 to 0.62 mm (p=0.026). The accuracy at the posterior skull base improved from 1.46 to 0.71 mm (p=0.014). The accuracy at the lamina was not significantly changed. CONCLUSION: Intraoperative portable CT scanning with real-time IGS updates is feasible and likely would add little additional time. Accuracy is improved at the skull base. Prospective studies on actual patients are warranted.